Abstract

Cystic fibrosis (CF) is one of the most common genetic diseases, affecting approximately 70,000 people worldwide causing severe complications and often leading to early death. CF is caused by a mutation in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein which is responsible for fluid and ion transport through epithelial membranes maintaining the formation of a thin slippery mucous layer. CFTR mutations either lead to a trafficking defect where the CFTR protein does not reach the plasma membrane or a gating defect where CFTR protein at the plasma membrane does not function properly. Treatment of cystic fibrosis usually addresses the symptoms to overcome the complications of the disease such as pneumonia, lung infections, pancreatitis, maldigestion and infertility. Vertex pharmaceuticals has been interested in developing small molecules that have the ability to interact with mutated CFTR proteins, aiding in their delivery to the cell membrane and/or restoring their channel function. VX-770 is an orally bioavailable potentiator that has the ability to improve the gating activity and increasing the open probability of CFTR protein in patients carrying the G551D mutation. VX770, Ivacaftor, was recently approved by the US FDA after showing very good improvements in the lung function in CF patients with good safety profile. Our research is focusing on the synthesis of VX770 under mild conditions and formation of labeled derivatives to help in the understanding of its exact mode of action. Different methods were developed toward the synthesis of the two main components, LHS and RHS, of VX770 by using less harsh conditions for a short period of time. We were successfully able to make two photoaffinity labeled derivatives, aryl azide and benzophenone derivatives, which will be beneficial in tracking the drug molecule and revealing the exact site of interaction between the drug and the protein. Synthesis of VX770 fragments was is another focus of interest in our research as they will provide us with information about the best positions for further derivatization.

Highlights

  • Cystic fibrosis (CF) is one of the most common life-threatening genetic diseases among people of Caucasian origin. It is an autosomal recessive disorder characterized by a widespread dysfunction of exocrine glands in lungs and the gastrointestinal tract leading to severe complications and often early death.[1]

  • The CFTR glycoprotein is comprised of 1480 amino acids and is a member of the ATP-binding cassette (ABC) superfamily; it is a family of active transporters that use the energy of ATP hydrolysis to translocate ions across epithelial membranes based on concentration gradient.[5, 11]

  • Scheme 2: Synthesis of phenylamino malonate With compound 1 in hand, an intramolecular Friedel-Crafts type acylation reaction was needed to afford the quinolinone left hand side (LHS) ester (Scheme 3)

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Summary

Background

Cystic fibrosis (CF) is one of the most common life-threatening genetic diseases among people of Caucasian origin. It is an autosomal recessive disorder characterized by a widespread dysfunction of exocrine glands in lungs and the gastrointestinal tract leading to severe complications and often early death.[1]. In the 1950’s, it was noted by Kessler and Andersen that cystic fibrosis patients show an abnormal electrolyte composition of the sweat (excess NaCl).[42]. Further investigations suggested that the disturbance in fluids and electrolyte transport is associated to an abnormally low chloride ion permeability through epithelial membranes that leads to poor NaCl reabsorption in sweat ducts and high concentration of NaCl in the sweat of cystic fibrosis patients.[3]. The CFTR glycoprotein is comprised of 1480 amino acids and is a member of the ATP-binding cassette (ABC) superfamily; it is a family of active transporters that use the energy of ATP hydrolysis to translocate ions across epithelial membranes based on concentration gradient.[5, 11]

Structure and Function of CFTR Protein
CFTR Acting as A Multifunctional Protein
Normal CFTR Protein Synthesis
Class I Mutations
Class II Mutations
Class III Mutations
Class IV Mutations
Class V Mutations
Symptoms of Cystic Fibrosis
Towards The Treatment of CF
Small Molecule Therapy
VX770: In the late 1990’s, Vertex
Labeled Derivatives
Synthesis of VX770
Research Objectives
Results and Discussion
First Approach
High boiling point solvents
Second Approach
Third Approach
Fourth Approach
Towards the Synthesis of 5-amino-2,4-di-tert-butyl phenol (RHS): The
Introduction of a bulky group
Introduction of an electron withdrawing group
Blocking the ortho position on the RHS
Synthesis of VX770 fragments
Towards the Synthesis of
Synthesis of Benzophenone Photoaffinity Label
Synthesis of Trifluoromethyl Diazirine Photoaffinity Label
Second approach
Synthesis of Tritium Radio Label
Conclusion
Full Text
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